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Publications

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We used biophysical methods to quantify BRAF dimerization and build an allosteric model of inhibitor-induced BRAF activation. We found that inhibitors selectively induce BRAF dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors.

Rasmussen et al., eLife 2024

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Working with Gunda Georg's group we used our biophysical techniques to profile the conformational effects of allosteric Cdk2 inhibitors. The results highlighted that these inhibitors must displace the cyclin subunit in order to bind to Cdk2:cyclin complexes, with important implications for the cellular setting in which they are likely to be effective.

Faber et al., Nature Communications 2023

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We used a combination of double electron-electron resonance (DEER) spectroscopy, paramagnetic relaxation enhancement NMR, and fluorescence to study allosteric activation of cyclin-dependent kinase 2 in solution. We showed that phosphorylation of Cdk2 on the activation loop enhances allosteric coupling between the cyclin subunit and the kinase, and demonstrate that this allosteric coupling underlies the selective recognition of CDK inhibitors.

Majumdar et al., Nature Chemical Biology 2021

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In this work with Lionel Pintard and Frank Sicheri's groups we helped identify a TPX2-like element in the Aurora kinase A activator Bora. This interaction is required for Plk1 phosphorylation and mitotic entry.

Tavernier et al., Nature Communications 2021

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The protein kinase Aurora A (AurA) is essential for the formation of bipolar mitotic spindles in all eukaryotic organisms. During spindle assembly, AurA is activated through two different pathways operating at centrosomes and on spindle microtubules. Recent studies have revealed that these pathways activate AurA through multifaceted changes to the structure and dynamics of the kinase domain.

Levinson et al., Biochemical Journal 2018

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We used a new time-resolved FRET based method to profile the conformational effects of a large panel of Aurora kinase inhibitors on Aurora A. The results show clearly for the first time that the preference of inhibitors for the DFG-in or DFG-out states is the dominant determinant of selectivity, and that different DFG-out inhibitors differ by two orders of magnitude in their preference for the DFG-out state.

Lake et al., Proceedings of the National Academy of Sciences  2018

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We used a diverse range of spectroscopic methods combined with long timescale molecular dynamics simulations to show that phosphorylation of the activation loop does not trap Aurora kinase A in the active DFG-in state as previously thought, and that the loop instead continues to transition between the DFG-in and DFG-out states.

Ruff et al., eLife 2018

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We used an infrared probe to show that allosteric activation of the mitotic kinase Aurora A by the spindle-associated protein Tpx2 is a two-step process, involving both a conformatonal shift towards the active DFG-In state, and an enhancement of the intrinsic activity of the DFG-In state through tuning of a novel allosteric network mediated by structured water molecules.

Cyphers et al., Nature Chemical Biology 2017

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Type I kinase inhibitors exploit structured water molecules in the ATP-binding site to recognize their kinase targets. These interactions turn out to be energetically significant and make a big contribution to the selectivity that inhibitors display for different kinases.

Levinson et al., Nature Chemical Biology 2014

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Bosutinib is a second-generation Abl kinase inhibitor used in the treatment of chronic myeloid leukemia. We determined the first crystal structure of this drug bound to the Abl kinase domain. The structure explains the effects of several resistance mutations that arise in patients during tyrosine kinase inhibitor therapy.

Levinson et al., PLoS ONE 2012

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The distantly related tyrosine kinases Src and Abl were previously thought to have unrelated allosteric activation mechanisms. Here we showed that Abl can in fact adopt an inactive conformation that looks almost identical to the canonical inactive conformation of Src, demonstrating that the conformational states that protein kinases adopt are broadly conserved across this protein family.

Levinson et al., PLoS Biology 2006

Selected publications on kinase structure and dynamics

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